This application requests continuation of a Research Scientist Award (K05). The broadest objectives are to understand why people take psychoactive drugs, what are expected or desired effects, what might account for unexpected or adverse consequences, and how can adverse consequences best be managed or prevented. How might tolerance and dependence determine differences in drug use and effects? How useful is phamacokinetic information for understanding differences in drug response? With support from other NIDA grants and contracts human laboratory experiments will study the pharmacokinetics and pharmacodynamics of cocaine, methamphetamine, cannabinoids 3,4-methylene-dioxymethamphetamine (MDMA) and interactions with other drugs. The cardiovascular, autonomic, neuroendocrine and subjective effects of MDMA and related of substituted phenethylamines will be compared to lysergic acid diethylamide (LSD). Modification of cocaine and methamphetamine tolerance and sensitization by new treatment medications will be studied. The pharmacokinetics of deuterium-labeled methamphetamine and tetrahydrocannabinol in hair and sweat will be characterized to better understand mechanisms and utility of hair and sweat for biomarkers of drug exposure. We will characterize the pharmacokinetics and dynamics of medications under development for pharmacotherapy of stimulant and other drug dependence in Phase I experiments. As possible, equal attention is given to psychological and behavioral measures, assessment of mood, neurophysiological and neurochemical indices. Emphasis is on understanding relationships between behavioral, physiologic and pharmacologic variables. Recognizing that people rarely limit drug taking to a single drug or class of drugs, development and application of research strategies appropriate to the study of multiple classes of drugs is preferred. Where possible, mechanisms and explanations for individual differences in drug effects are studied. Relationships between naturally occurring and drug-induced disorders, for example, depression, anxiety states and schizophrenia or other psychosis is a topic of interest. The studies are multidisciplinary. They involve only human volunteers. The research will further understanding psychoactive drug use, health consequences and management.